Genetic Variant CELF2:p.Arg506Leu (chr10-11329004-G-T) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PM5PP3PP5_Moderate

The NM_001326342.2(CELF2):c.1517G>T(p.Arg506Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R506G) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

CELF2
NM_001326342.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 10.0

Publications

0 publications found

Variant links:

Genes affected

CELF2 (HGNC:2550): (CUGBP Elav-like family member 2) Members of the CELF/BRUNOL protein family contain two N-terminal RNA recognition motif (RRM) domains, one C-terminal RRM domain, and a divergent segment of 160-230 aa between the second and third RRM domains. Members of this protein family regulate pre-mRNA alternative splicing and may also be involved in mRNA editing, and translation. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

CELF2 links:

CELF2-AS1 (HGNC:23515): (CELF2 antisense RNA 1) Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

CELF2-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr10-11329003-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 1299464.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.808

PP5

Variant 10-11329004-G-T is Pathogenic according to our data. Variant chr10-11329004-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 2579922.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001326342.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CELF2	NM_001326342.2	MANE Select	c.1517G>T	p.Arg506Leu	missense	Exon 13 of 13	NP_001313271.1	E9PC62
CELF2	NM_001326325.2		c.1571G>T	p.Arg524Leu	missense	Exon 15 of 16	NP_001313254.1
CELF2	NM_001326343.2		c.1571G>T	p.Arg524Leu	missense	Exon 14 of 14	NP_001313272.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CELF2	ENST00000633077.2	TSL:1 MANE Select	c.1517G>T	p.Arg506Leu	missense	Exon 13 of 13	ENSP00000488690.1	E9PC62
CELF2	ENST00000632065.1	TSL:1	c.1553G>T	p.Arg518Leu	missense	Exon 14 of 14	ENSP00000488422.1	A0A0J9YXJ0
CELF2	ENST00000542579.5	TSL:1	c.1517G>T	p.Arg506Leu	missense	Exon 13 of 14	ENSP00000443926.1	E9PC62

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

M_CAP

Benign

0.060

MetaRNN

Pathogenic

0.81

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

PhyloP100

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-6.5

REVEL

Uncertain

0.49

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

0.57

Vest4

0.83

MutPred

0.62

Loss of disorder (P = 0.0434)

MVP

0.88

ClinPred

1.0

GERP RS

5.0

Varity_R

0.76

gMVP

0.94

Mutation Taster

=20/80

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over